Isocyanate-induced
asthma, which is the most common type of
occupational asthma, has been difficult to diagnose and control, in part, because the
biological mechanisms responsible for the disease and the determinants of exposure are not fully defined. To help address these issues, we recently established a murine model of
toluene diisocyanate (TDI)
asthma using inhalation exposure paradigms consistent with potential workplace exposure. In order to confirm our hypothesis that TDI-induce
asthma, like allergic
asthma, is predominantly a Th2 response, the ability of mice that were deficient in CD4 or CD8 cells or specific Th1 and Th2
cytokines to develop TDI
asthma was examined. The development of allergic
asthma was evaluated by monitoring lungs for the presence of
eosinophilia, goblet cell
metaplasia, epithelial cell alterations, airway hyperreactivity (AHR), and Th2 and Th1
cytokine expression, as well as serum
IgE levels and TDI-specific
IgG antibodies. Transgenic CD8 or CD4 knockout (KO) mice exhibited significant reductions in AHR,
cytokine expression, serum antibody levels, airway
inflammation, and histopathological lesions, although in a number of the endpoints the effects were more attenuated in CD4 KO mice. IFNgamma depletion ablated the increase in AHR in TDI-allergic mice, but had only slight to moderate effects on airway histopathology, serum antibody levels, and
cytokine expression compared to sensitized/challenged controls.
IL-4 and
IL-13 deficiency had moderate inhibitory effects, while combined IL-4/
IL-13 depletion effectively prevented almost all
asthma-associated pathologies. Taken together, these results indicate that TDI
asthma, like immune-mediated
asthma produced by large-molecular-weight materials, is driven primarily by CD4+ T cells and is dependent upon the expression of Th2
cytokines. However, as with
protein-induced
asthma models, certain pathologies are influenced by CD8+ T cells and Th1-derived
cytokines, such as AHR and
cytokine production.